The principal neurological complication of HIV/AIDS observed in the developed world is currently peripheral neuropathy, usually manifested as distal polyneuropathy (DSP) or antiretroviral toxic neuropathy (ATN). This proposal examines the role of lentivirus molecular diversity in relation to the development of DSP, using multiple infectious biological strains and recombinant viruses of feline immunodeficiency virus (FIV). Based on our preliminary studies and earlier reports, we hypothesize that infection of peripheral nerves by select FIV strains, expressing different env sequence contributes to the development of DSP due to immune activation within the nerve together with concomitant systemic immune suppression. Moreover, viral heterogeneity and load within the nerve determine the severity of DSP, which can be abrogated or exacerbated with specific antiretroviral drugs. To investigate the mechanisms by which viral diversity contributes to DSP, we propose to use a well defined in vivo model of lentivirus infection in which animals infected with different strains or molecular clones of FIV are assessed neurobehaviorally, electrophysiologically, morphologically and immunologically in conjunction with analyses of viral heterogeneity and load in peripheral nerve and other organs. To support these in vivo studies, we will also explore the role of FIV env-mediated neurotoxicity using a dorsal root ganglia-derived culture system, allowing us to dissect the relative contributions of individual cell types to the pathogenesis of DSP including macrophages and Schwann cells. From these studies, we expect to gain insights into this common neurological complication in terms of lentivirus-induced neurovirulence and pathogenic host responses.